Balancing Neuroprotection with Functional Recovery: The Role of the Perineuronal Net in Preventing Excitotoxicity after Spinal Cord Injury
Grade Level at Time of Presentation
Senior
Major
Neuroscience
Minor
Biology, Italian
Institution
University of Kentucky
KY House District #
88
KY Senate District #
12
Faculty Advisor/ Mentor
Warren Alilain
Department
Department of Neuroscience
Abstract
In spinal cord injury (SCI), initial mechanical trauma causes debilitating primary damage to neural cells and blood vessels. Following this, secondary cascades of downstream events occur, including inflammation, ischemia, and excitotoxicity — an increase in intracellular Ca2+ concentration from overactive glutamate (Glu) receptor activity leading to cell death. Additionally, there is an upregulation of the perineuronal net (PNN), a lattice-like structure of the extracellular matrix which modulates neural communication and homeostasis. The PNN is partially composed of negatively charged chondroitin sulfate proteoglycans (CSPGs). While the PNN and CSPGs can support plasticity and neuronal growth during development, after injury these ECM molecules are inhibitory to regeneration, sprouting and plasticity. However, administration of the bacterial enzyme chondroitinase ABC (ChABC) can digest these inhibitory factors and promote functional recovery. What remains unknown is the impact of removing these inhibitory factors soon after injury. We hypothesize that negatively charged CSPGs are upregulated after SCI as a neuroprotective response that attenuates excitotoxicity by acting as a sink for Ca2+. To test our hypothesis, we induced excitotoxicity by injecting rats with a threshold dose of Glu with or without ChABC utilizing the well defined respiratory motor system. 59% of SCI occurs at the cervical level, and leading causes of death and restriction of independence in these cases stem from mechanical ventilation. Therefore, we administered the dose instraspinally at the C4 level and paired treatment with intrapleural injection of cholera toxin-B to retrogradely label the phrenic motor neuron pool which innervates the diaphragm. our early findings suggest that animals treated with both Glu and ChABC had more extensive cell death. We believe this implies that following SCI, the body’s main focus is to survive and not necessarily to preserve function. CSPG upregulation could promote survival and CNS tissue preservation at the expense of plasticity and functional regeneration.
Balancing Neuroprotection with Functional Recovery: The Role of the Perineuronal Net in Preventing Excitotoxicity after Spinal Cord Injury
In spinal cord injury (SCI), initial mechanical trauma causes debilitating primary damage to neural cells and blood vessels. Following this, secondary cascades of downstream events occur, including inflammation, ischemia, and excitotoxicity — an increase in intracellular Ca2+ concentration from overactive glutamate (Glu) receptor activity leading to cell death. Additionally, there is an upregulation of the perineuronal net (PNN), a lattice-like structure of the extracellular matrix which modulates neural communication and homeostasis. The PNN is partially composed of negatively charged chondroitin sulfate proteoglycans (CSPGs). While the PNN and CSPGs can support plasticity and neuronal growth during development, after injury these ECM molecules are inhibitory to regeneration, sprouting and plasticity. However, administration of the bacterial enzyme chondroitinase ABC (ChABC) can digest these inhibitory factors and promote functional recovery. What remains unknown is the impact of removing these inhibitory factors soon after injury. We hypothesize that negatively charged CSPGs are upregulated after SCI as a neuroprotective response that attenuates excitotoxicity by acting as a sink for Ca2+. To test our hypothesis, we induced excitotoxicity by injecting rats with a threshold dose of Glu with or without ChABC utilizing the well defined respiratory motor system. 59% of SCI occurs at the cervical level, and leading causes of death and restriction of independence in these cases stem from mechanical ventilation. Therefore, we administered the dose instraspinally at the C4 level and paired treatment with intrapleural injection of cholera toxin-B to retrogradely label the phrenic motor neuron pool which innervates the diaphragm. our early findings suggest that animals treated with both Glu and ChABC had more extensive cell death. We believe this implies that following SCI, the body’s main focus is to survive and not necessarily to preserve function. CSPG upregulation could promote survival and CNS tissue preservation at the expense of plasticity and functional regeneration.